PROJECT SUMMARY Yersinia pestis, the causative agent of plague, has profoundly shaped human history by causing an estimated 200 million deaths amid three major pandemics. Considered to be a re-emerging pathogen, Y. pestis remains a public health issue and is responsible for several thousand worldwide annual cases of plague. Endemic plague foci persist through zoonotic circulation among rodent reservoir hosts and flea vectors. In addition to natural flea-borne acquisition, Y. pestis has an extensive history of biological warfare manipulations and is categorized as a prime threat for modern weaponization. Pneumonic plague, the most acute and threatening manifestation, is highly contagious and easily transmitted from person-to-person through airborne droplets, resulting in a rapid onset of disease and a mortality rate approaching 100% if treatment is delayed 24 hours beyond symptom onset. Currently, no licensed plague vaccines are available in the United States. Yersiniosis refers to an enteric infection by species of the genus Yersinia. There are two subtypes responsible for yersiniosis, Yersinia enterocolitica (Ye) and Yersinia pseudotuberculosis (Yptb). Ye and Yptb are fecal-oral zoonotic pathogens which ciruclate among environmental and a broad range of animal reserviors. Through incidental food-borne exposure, humans can develop yersiniosis, potentially culminating in systemic infection and postinfectious extraintestinal sequelae. In addition to direct human health risks, yersiniosis confers a considerable food-safety economic burden and is responsible for substantial livestock production loss. However, limited attention has been devoted toward vaccine development for yersiniosis. We have previously made substantial headway in the construction of a recombinant Yptb vector vaccine candidate aimed at preventing both plague and yersiniosis. Based upon our established recombinant attenuated Salmonella vaccine platform, a Yptb-based vaccine against plague and yersiniosis will impart several key advantages including (1) needle-free oral administration, (1) low-cost vaccine production, and (3) robust induction of humoral and cellular immune responses, and (4) human and environmental bait delivery. Additionally, we strive to elicit protective immunity upon a single dose without adjuvant supplementation. We previously demonstrated that immunization with attenuated Yptb strains elicits cross-protection against Y. pestis and Ye. Furthermore, immunogenicity against Y. pestis is readily enhanced by type 3 secretion system delivering heterologous antigens. Therefore, immunization with improved live attenuated Yptb strains shall stimulate cross-protective immunity against Y. pestis causing plague, and Ye and Yptb causing yersinosis.